Animal models are useful for testing and developing future treatments and procedures before they are tried in humans. Before bone marrow transplants were first tried clinically in the 1950’s for the treatment of radiation poisoning or leukemia, they had already been shown to work in rats, dogs, and primates. But even after the proven success of the method to replenish a patient’s hematopoietic stem cells - the precursors of all the different types of blood cells - animal models continued to be useful for improving the procedure and better understanding the system’s biology. Now, more than 50 years after those first experiments, a new animal model for transplanting marrow has been developed - under water.

Zebrafish, the tiny, striped fish often found in pet stores, lead a double life as scientific heroes. Because of their fast reproductive cycle, translucent embryos (seen above), and well-studied genome, zebrafish are an increasingly popular animal model for scientists to study embryonic development, genetics, and diseases such as cancer. The ability to easily mutate zebrafish genes and screen for interesting biological changes makes the species an ideal fit for studying the function of hematopoietic stem cells and how they can be better used in medical procedures. But there was only one problem for a team of researchers at the Harvard Stem Cell Institute: nobody had tried to do a marrow transplant in zebrafish before.

“We wanted to be able to have an assay where you could compare mutant marrow with wild type marrow and see whether the hematopoietic stem cells function differently,” said Jill de Jong, member of the Harvard research team and now assistant professor of pediatrics at the University of Chicago Medical Center. “The only way to do that was with a transplant assay. Since you’re talking about mutants in fish, it really would have to be a transplant assay in fish - and that didn’t exist.”

Translating a stem cell transplant procedure developed in mammals to fish required several modifications. For one, zebrafish do not carry their hematopoietic stem cells in bone marrow, but rather in their kidneys. In recipient fish, nobody had calibrated the amount of radiation needed to knock out the native marrow cells, or the amount of donor cells needed to successfully replenish the marrow and blood. And while it is easy to match mice for transplantation purposes - because they are inbred and immunologically identical - the fish require more precise matching of donor and recipient, just like humans. The low success rate in the first batch of zebrafish transplants reflected this difficulty.

“These fish were like random donors, they were not immunologically matched at all,” de Jong said. “In some ways, it’s kind of miraculous that it even worked at all.”

But one by one, the kinks were worked out and the procedure was standardized (and published earlier this year in the journal Blood). A number of the immune system MHC genes, which are carefully matched in human bone marrow transplants, were located on chromosome 19 of the zebrafish genome. Each fish could then be genotyped and paired with a closer match for the transplant, which raised the success rate of the procedure.

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The University of Chicago is the birthplace of nuclear energy. So like proud but concerned parents, UChicago has kept a close eye on the benefits and challenges of nuclear power over the years since the first self-sustained nuclear reaction under Stagg Field. Thus, the battle to manage the consequences of the damaged reactors at the Fukushima I Nuclear Power Plant in Japan has drawn the University’s interest, and the short-term and long-term effects of that ongoing situation were the subject of a unique panel held on campus yesterday, “Lessons from Fukushima.”

Though nuclear power was created by scientists, discussing its use requires input from political and economic spheres as well. So the panel, assembled by the University of Chicago Alumni Association, brought together nuclear technologists (Hussein Khalil, director of the nuclear energy division at Argonne National Laboratory, and Mark Peters, deputy director of Argonne), nuclear policy watchdogs (Kennette Benedict, executive director of the UChicago-based Bulletin of Atomic Scientists), and energy economics experts (Robert Topel, director of the University of Chicago Energy Initiative). With such different perspectives, it didn’t take long for the panelists to find points of debate, reflecting the tug-of-war over nuclear power that has gone on for several decades.

Nobody disputed the magnitude of the Fukushima incident, with workers at the plant still struggling to limit core meltdown in at least three of the reactors as well as re-cooling spent fuel rods at the site. As well, the panelists agreed that the incident was very relevant to nuclear power in the United States, where roughly one-fifth of electricity is provided by nuclear plants, many of which use the same model as the Fukushima reactors. But opinions differed on what those consequences would be.

Khalil pointed out that this was the first natural disaster to cause “grave damage” to a nuclear power plant in nearly 60 years of their use, and that a similar occurrence was very unlikely in the United States. But Benedict argued that “very unlikely” wasn’t good enough for “the most dangerous technology on Earth,” and that not every safety precaution possible had been taken at Fukushima. Topel agreed with the latter point - “why build generators on the ocean side in a country that coined the term ‘tsunami’?” he asked - and noted that the renewed attention to the long-term dangers of nuclear power would only make it more difficult to build new reactors.

In fact, no new nuclear reactor has come online in the United States in 32 years, Khalil said. So while Argonne continues to research new designs for nuclear plants and new strategies for containing nuclear waste, the economic (and possibly now public opinion) barriers are too large. The most likely rescue for nuclear power may come from an unlikely source: climate change.

“If other technologies turn out to be a bust, and if we really are serious about reducing our carbon footprint and carbon pricing becomes important, then there is a technology we have that can produce a lot of energy at relatively low cost compared to the alternatives,” Topel said. “Then, nuclear energy will prosper.”

By the end of the 90-minute discussion, the panelists came back to common ground on a hopeful note. If a thin silver lining could be found on a disaster that hasn’t yet been completely averted, it’s that the events at Fukushima have re-opened the international dialogue on nuclear power - its immense benefits and equally immense costs.

“One of the positive externalities of the Fukushima accident is that many more people are interested in nuclear energy, and I think that’s terrific,” Benedict said. “It’s unfortunate that it takes an accident to do it.”

Elsewhere…

The conversation about cancer is changing, from a single disease classified by the organ where it appears to multiple diseases grouped by genetic and biological similarities. As ScienceLife has written before, the Chicago Cancer Genome Project is our local contribution to this strategic shift against “the emperor of all maladies.” This week the Los Angeles Times examined that research effort and others like it, speaking with project leader Kevin White and many of the Medical Center’s cancer experts collaborating on this new vision of how to classify and battle cancer.

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There are many different stakeholders in fixing the runaway costs of the U.S. health care system, including patients, doctors, hospitals, and the federal government. Another interested party, heavily involved in recent debates over health care reform, is the health insurance industry. As the Patient Protection and Affordable Care Act rolls out in the coming years, insurance companies will need to adapt to many new rules and regulations on matters such as pre-existing conditions and insurance exchanges. But they also have their own ideas about how to reduce health care costs, focusing on two key components of PPACA: health disparities and quality improvement.

Aetna is the third largest insurance provider in the United States, providing medical insurance for more than 17 million people. The Aetna Foundation, their charity and grant-dispensing arm, is focused on promoting wellness, health, and access to high-quality health care. Addressing those goals will also make progress in reducing health disparities, said Anne Beal, president of the Aetna Foundation, in her presentation to the MacLean Center for Clinical Medical Ethics. The strategy she outlined showed how parties who have sometimes been at odds in the health care reform debate can find common ground for the benefit of patients.

Beal, formerly a faculty researcher at Massachusetts General Hospital and the co-author of a best-selling parenting book, made a case for health equity to the seminar series, which this year is themed “Health Disparities: Local, National, Global.” Beal presented now-familiar statistics about higher rates of infant mortality, diabetes, and more in minority communities, but added a new voice to the mix - the words of Martin Luther King, spoken in Chicago in 1966: “Of all the forms of inequality, injustice in health care is the most shocking and inhumane.”

But aside from social justice, there’s also a bottom-line argument to be made for reducing health disparities, Beal said. If you think of disparities as a form of inefficiency in the health care system, billions of dollars could be saved by narrowing those gaps.

“When you talk about health disparities, it is an important opportunity for us to really try to bend the cost curve,” Beal said. “Giving people the right care at the right time and preventing disease is an amazing way for us to really rein back a lot of these health care costs.”

Ensuring that people receive appropriate care falls under the domain of quality improvement (QI), the idea that health outcomes can benefit from fewer mistakes and more efficient delivery of care. Beal admitted that quality improvement was just one of many possible causes of health disparities, but argued that QI was a way to improve care for all patients and reduce health disparities at the same time - a win-win situation, if done right. Simple interventions such as making sure patients receive the right hemodialysis dose or even basic vaccination programs can help overall population health while narrowing the gap between white populations and minorities.

“This is not to say we shouldn’t do special interventions and targeted population efforts and things like that, but we need to stick to the basics,” Beal said. “If you can’t look at a population of children and say that they’re 100 percent vaccinated against measles, then any other intervention you do is just trying to put a band-aid on a bad situation. I would argue that we really need to focus on high quality care as the first step for addressing population health in communities of color.”

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It’s no big secret that one of the keys to good health is getting regular exercise. Yet good intentions are often thwarted by factors outside of one’s control. A person might decide to jog or bike several times a week, but if the neighborhood outside their door is not conducive to physical activity, it can be easier said than done. Whether you live out in the country or deep in the heart of the city, the design of the neighborhood around you can have an effect on your ability to exercise out of doors.

To clarify that relationship between neighborhood streets and physical activity, epidemiologist Ningqi Hou used data from one of the largest longitudinal studies of cardiovascular health in the United States, the CARDIA study. As a graduate student at the University of North Carolina, Hou and her colleagues analyzed the frequency of physical activity in over 5,000 CARDIA participants alongside characteristics of the “street networks” where they live. Hou, now a postdoctoral researcher in the Department of Health Studies at the Medical Center, looked at the density of intersections, the connectivity of streets, and the type of roads in each participant’s neighborhood.

Their hypothesis was that the “built environment,” the infrastructure surrounding a person’s home, has an invisible influence on their behavior that could conflict with their exercise plans.

“Although there are a lot of physical activity interventions, a lot of them don’t actually work. For example, you have an education program to tell people how beneficial physical activity could be, but over time, that effect is going to fade,” Hou said. “However, your built environment is really just existing there for you, and you are passively receiving its influences. To build a sustainable intervention, you need to know what works in that environment.”

The results of the analysis, published in December in Health & Place, were more complex than just “more roads, more exercise.” In areas of low urbanicity - rural and exurb regions with small, spread out populations - more connected street networks did indeed promote walking, jogging, and bicycling. Specifically, a higher density of intersections was associated with more outdoor exercise, suggesting that long, country roads are better suited to physical activity when they are connected instead of remote. That information could be valuable for civic planners looking to build “exurban” neighborhoods that promote health, instead of sprawling suburbs filled with meandering drives and cul de sacs.

“For the ongoing projects we can still influence that process and hopefully help planners to build a more physical activity-friendly environment,” Hou said. “Sometimes when I see the cookie-cutter communities, they have a very suburban style of being spread out, and it kind of worries me. But I think our result may do some good in informing policymakers to change the design for new communities.”

But in more densely packed areas of high urbanicity, the street network effect reversed for women. The higher the density of local roads, the less often female residents biked, jogged, or walked on average (men were unaffected). This unexpected result suggested that other factors associated with high population and street density - such as crime, or socioeconomics - could counteract the exercise benefits of a more connected neighborhood, Hou said. It also suggests that changing urban neighborhoods to promote physical activity may be more complex than adding intersections.

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The benefits of measuring body mass index (BMI) are clear: a physician who knows a patient’s BMI is more likely to counsel her on lifestyle changes, and people are more likely to try diet and exercise on a doctor’s advice. But in the often-rushed environment of the clinic, even the quick calculations required to know a patient’s BMI can get lost in the shuffle.

Internal medicine residents at the Medical Center noticed that almost none of their patients had a BMI recorded on their charts, but many of their patients seemed overweight and obese.

“They initially wanted to improve obesity rates in patients,” said Vineet Arora, MD, who participates in teaching a quality improvement curriculum to residents and is senior author of a study. “But we needed something feasible. Recording and calculating most patients’ BMI was something they could change.”

Their quality improvement initiative and a study about it, published online in March in the American Journal of Medical Quality, grew out of the quality improvement education that all residents now receive at the University of Chicago.

Neda Laiteerapong, MD, was an internal medicine resident at the University of Chicago Medical Center when she decided that measuring BMI was vital to improving patient care. “We couldn’t even identify who was obese in our clinic. If you don’t identify it, you’re not going to treat it on a patient-by-patient basis,” she said.

Laiteerapong and nine of her fellow residents looked at the triage of patients in the clinic, and decided that they could easily make a few small changes to the vital signs that nurses record when a patient is checked in. “Most clinics weigh people, but they don’t measure height,” Laiteerapong said, noting that the combination of height and weight is usually only measured in children. She also said that asking a patient his height isn’t an accurate way to calculate BMI, since people often overestimate how tall they are.

The residents added rulers in the clinics, height and weight charts in the patient rooms, and a slot on the patient intake form for BMI. The nurses took the measurements, and the residents were responsible for calculating BMI. Within a month, the number of patients with a recorded BMI jumped from 4% to 80%.

Julie Oyler, MD, assistant professor of medicine and associate program director for the internal medicine residency, implemented the quality improvement curriculum for residents in 2006. “I would consider this a successful project,” she said. “Instead of complaining about poor practices in a clinic, the residents are getting experience changing and fixing the clinics.”

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TED Comes to Campus

This weekend, the students of the University of Chicago are putting together a local edition of the renowned TED conference called TEDxUChicago. The theme, “Reinventing the Life of the Mind,” nicely blends the goals of TED and the University, the idea-sharing mission of the conference sutured to the intellectual spirit of our campus. Among the talks taking place at the Reynolds Club this Sunday are a few UChicago scientists: paleontologist and educator Paul Sereno (speaking on the topic of “Art In Science”), psychologist and child language expert Susan Goldin-Meadow (”What Our Hands Can Tell Us About Our Minds”), and student speaking contest winner Bruno Cabral (“The Life of the Mind Lived Through Noise”), an undergraduate working in the laboratory of psychologist Howard Nusbaum. Other speakers include Mark Inglis, the first double amputee to climb Mount Everest, Jonathan Greenblatt, the former CEO of GOOD magazine, and cybernetics expert Kevin Warwick giving probably the talk with the coolest title: “The Last Remaining Hurdles to Cyborg Technology.” Tickets are still for sale on the TEDxUChicago website, but if you can’t make it down to Hyde Park, the talks will be webcast live at the UChicago Facebook page.

The Rules of Language

Last week, the Joseph P. Kennedy Intellectual and Developmental Diabetes Research Center held a symposium called “Variations in Language Learning,” a series of talks about how languages are acquired by children, adults, and cultures. Elissa Newport, a professor of brain & cognitive sciences and linguistics at the University of Rochester, presented fascinating data on the concept of “statistical learning,” the theory that the brain uses mathematical tricks to learn the arcane rules of a new language. To test this idea, Newport and her colleagues played a made-up language of nonsense syllables for 20 minutes (!) to volunteers, showing that combinations of syllables that show up more frequently (such as “dutaba” or “babupu”) are eventually perceived as “words” by the listener. The researchers also went on to show that children are better at this “statistical learning” than adults when confronted with a new language, offering an explanation for why languages are easier to pick up when learned at a younger age.

The idea of a universal foundation for learning and developing language echoes the “universal grammar” theories of Noam Chomsky and others, if peripherally so - Newport’s experiments showing that the same statistical learning can be used for tones and visual sequences implies that it’s a universal learning mechanism, not specific to language. But a new phylogenetic analysis of the world’s languages appearing in Nature this week argues against innate rules for language, demonstrating deep grammatical differences between “families” of languages go against the idea of a universal human grammar. Most linguists seem skeptical or underwhelmed about the result, and the debate smacks of a false dichotomy, with the truth about language development less a battle between cognition and culture than a combination of the two forces. Discover, the LA Times’ Amina Khan, and Ars Technica’s John Timmer all weigh in on the study.

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There are few biological functions that we take for granted more than gait, the intricate symphony of motion that happens almost automatically when we walk or run. Gait is programmed deep into the nervous system of animals, an activity so robust that it is maintained even when large segments of brain are removed. Those crude, early experiments suggested that the machinery for gait was somehow packed into the spinal cord. But scientists are still mapping the networks of neurons - called central pattern generators - that give fish, mice, and men the ability to propel themselves forward at slow or fast speed.

For the past 5 years, the laboratory of Kamal Sharma, associate professor of neurobiology at the University of Chicago, has been looking at one key component of this gait machinery: the V2a interneuron. Interneurons are the go-betweens of the spinal cord, coordinating the message between the motor and sensory systems. In animals with a gait that alternates left and right feet as they walk or run, interneurons are a likely candidate for coordinating this action - suppressing the left limb as the right moves forward, and vice versa. So after a paper identified the developmental background of the V2a interneurons, Sharma and postdoctoral researcher Steven Crone began studying whether these cells were in fact an important component of the gait system.

The quickest way to determine a cell type’s importance is to remove it, and that’s just what Crone did in a 2009 paper - genetically inserting a toxin that kills V2a interneurons. Other than appearing smaller than their wild-type peers, the mice without the neurons seem to be fairly normal. When placed on treadmills running at a slow speed, the modified mice alternate left and right paws just as the normal mice did. But when the treadmill was sped up, a difference was revealed - where normal mice continued alternating left and right at a faster pace, mice lacking V2a interneurons broke out into a “gallop,” moving left and right limbs together.

That result suggested that the system controlling gait at slow speeds may differ from the gait system when an animal is traveling at faster speed. That dynamic has been seen in other animals, such as the zebrafish, where different spinal cord interneurons are active when swimming at high speed compared to low speed.

“The question is when you are walking slow versus when you are walking fast, do you use the same neurons that are firing at different speeds, or are you actually recruiting more neurons?,” Sharma said.

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Photo by Gerald Waddell

At ScienceLife HQ, we often hear the loud roar of the hospital helicopter as it takes off on urgent duty. In this article that originally appeared in the Medical Center publications Newsfront and Forefront, Cheryl L. Reed writes about what motivates and amazes the nurses who fly those missions. You can watch a video version of the story here.

From a distance it sounds like thunder and then like a rogue train plowing through the neighborhood. But closer in, the rumbling in the sky is unmistakable, a helicopter, its blades splicing the air. Within sight, the maroon helicopter becomes a point of pride and curiosity: What crisis are University of Chicago Medical Center nurses and emergency residents responding to? Is it a car crash or a woman in premature labor? Are they transporting organs for transplant surgery or ferrying a complex patient whose symptoms can’t be unraveled by doctors elsewhere?

When the helicopter lands and the noise dies down, the crew from University of Chicago Aeromedical Network (UCAN) emerge in their flight suits looking much like characters from the movie Top Gun.

“I usually get stopped at least once a week in a hospital by someone who asks me how I got my job,” said Kelley Holdren, BSN, CFRN, who has been a UCAN flight nurse for seven years.

The Medical Center’s UCAN program was the first and remains the only hospital-based flight response in the Chicago area. Though air ambulances are common in Chicago, most are operated by private companies. UCAN started at the Medical Center in 1983. At the time, it was the 53rd flight program in the country and the only dedicated flight program in the Chicago area. Now, there are over 700 medical helicopters across the country.

UCAN runs 24 hours, seven days a week and has nine nurses, several of whom are part-time, and a crew of emergency medicine residents. At least one flight nurse and one resident are on every transport. Second- and third-year residents spend two years doing shifts in the flight program. The pilots are usually retired military. Ira Blumen, MD, is UCAN’s program and medical director and Karen Arndt, RN, BSN, CFRN, CMTE, is its chief flight nurse and administrative director.

“UCAN is a great program and a leader in the industry nationwide,” said Pat Petersen, executive director of the Air Medical Physicians Association (AMPA). “Ira Blumen was an original board member of AMPA and was the editor of a textbook about medical transport. He and Karen Arndt have done amazing things for the industry; their contributions to the safety reviews have been invaluable.”

Kelley Holdren on board the helicopter. (Photo by Cheryl L. Reed)

For Holdren, her job as a flight nurse is the culmination of a dream that began in sixth grade while sitting in her orthodontist’s office. Among the magazines scattered in the waiting room was one that featured a story about the UCAN program. Instantly, it hit her: “That’s what I want to do.”

On her honeymoon in Maui, she convinced her husband, who gets motion sickness, to take a helicopter ride to see if she could really handle being in the air. “It had become such a big part of my drive to become a flight nurse and, yet, I’d never even ridden in a helicopter,” she said.

When Holdren graduated from nursing school in 1997, she held out for a position at the Medical Center because her ultimate goal was to become a flight nurse. She started out in the Medical Intensive Care Unit and then moved to the Pediatric Intensive Care Unit (PICU). “It was all just a holding pattern until I could start flying,” she said.

Along the way, Holdren was coached by Arndt who encouraged the young nurse to expand her experience in the PICU and in cardiac care. “It’s pretty rare that someone leaves,” Arndt said, “but when they do there are always lots of people trying to get in.”

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In the 11 years since the blueprint of human life was decoded by the Human Genome Project, much of the focus has been on when those instructions fail. Scientists have used our newfound genetic knowledge to look for the roots of common and rare diseases, the gene or genes that can increase the risk of everything from heart disease to cancer to asthma. But setting the stage for future illness is not the purpose of genes, of course. By coding for the proteins that make up the body and brain, genes lay the foundation for everything we do, feel, and probably even think.

Like the study of disease, genetic studies of human behavior have mostly focused on the abnormal - the targets of psychiatry. Mental illnesses such as schizophrenia, depression, and drug addiction have been the subjects of genetic hunts, known as genome wide association studies, where the ill are compared to controls to reveal genes that might be involved in the a particular disorder. As with diseases in the rest of the body, psychiatric disorders have mostly resisted easy genetic explanations - only a small percentage of schizophrenia, for instance, has been traced to genetic causes.

A more useful, but also vastly more complicated, approach might be to study not the binary comparison of healthy vs. sick, but the whole spectrum of human behavior. For example, rather than just looking at those with extreme enough depression symptoms for a clinical diagnosis and those who don’t, scientists could look at genes in subjects who are rarely, mildly, or frequently affected by depression, as well as those on the extremes. Such analyses may get closer to the genes and brain structures that control human behavior, both in everyday life and when it breaks down.

These types of experiments have caught the imagination of Abraham Palmer, assistant professor of human genetics at the Medical Center. In collaboration with the laboratory of Harriet de Wit, professor of psychiatry, Palmer has started to look at the behavioral trait of impulsivity, which has been associated with attention deficit disorder and predisposition to drug abuse.

“We’re coming at it from a tradition that’s very psychology, drug abuse-based, but we’re really interested in asking questions that get at the broadest range possible of behaviors,” Palmer said. “These are continuous traits that everybody in the population will have some value for. We’re not talking about it exclusively from a disease perspective. These are healthy people coming in.”

Palmer used Donald Rumsfeld’s infamous quote about known knowns, known unknowns, and unknown unknowns, to illustrate how studies of genes and behavior have classically been limited by the tunnel vision of previous knowledge. If a particular gene is already known to play a role in a behavior, scientists can study how individual variants in that gene correspond to behavior. In one such project, Palmer was part of a team that looked at the D2 dopamine receptor - a neurotransmitter receptor linked with the response to drugs of abuse - and impulsive decision-making.

Volunteers came to the laboratory and performed a “stop task,” a common psychology test. The subject is trained to look for a “go signal” and start hitting a certain keyboard key as quickly as possible until the “stop signal” sounds. The delay between the go and stop signals is steadily decreased with each round, and the ability of the subject to stop on time is measured. Researchers then compared their D2 genotype to their behavioral score, and found a link between different D2 variants and more “impulsive” results on the stop task.

These results help researchers study possible genetic predisposition for drug abuse or addition. But Palmer said he wants to expand the search beyond genes that are already implicated in behaviors and beyond psychiatric conditions.

“We’ve mostly looked at candidate genes, genes where we had reason to think it might modulate a behavior,” Palmer said. “But the more interesting question, if you had a sufficiently large sample and enough power, is to say let’s go at this with a blank state, let’s look at all the polymorphisms in a genome and pull out novel things maybe in genes we had never thought to be related to these processes.”

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In physics, there’s nothing better than an unexpected result. Wednesday, Fermilab scientists unveiled the graph at left and caused figurative rioting in the streets of the physics community, confirming months of rumors about an exciting new result from the suburban Chicago facility (You can watch video of the presentation here). It’s a big score in the final days of Fermilab’s Tevatron accelerator, which is due to close later this year due to budget cuts and the ascendancy of the more powerful CERN Large Hadron Collider in Switzerland.

The buzzworthy peak was the result of collision experiments where Fermilab scientists expected to see a W boson and two quarks, elementary particles that are part of the Standard Model of physics. But the experiments produced something additional, something unexpected, something unusual: a bump. Particle physicists spend their whole life chasing bumps, as Sean Carroll of Fermilab explains at his Discover Magazine blog, because they are “often a signature of a new particle that has been produced and then quickly decayed.” The anomaly could thus be a previously undiscovered particle that is not predicted by the Standard Model (apparently it is too large to be the elusive Higgs boson), forcing a re-write of the core theory of modern physics. Even if it’s not a new particle, some say an incorrect prediction like this one could mean that some of the rules of the Standard Model may need to be tweaked.

But despite the excitement, caution still reigns - as Dennis Overbye wrote in the New York Times, “The key phrase, everyone agrees, is ‘if it holds up.’” The chance that it is just a statistical anomaly is less than 1 in 1375, the researchers said. With that kind of data, biologists (whose 1 in 20 standards were lampooned effectively by the science comic xkcd this week) would already be popping champagne, but it’s not good enough for physicists - past findings of that strength have disappeared with further scrutiny. If additional experiments still being analyzed push the chance of error to 1 in a million, the true celebration will begin, and the finding could be the most important piece of new physics in decades.

Scientific Shutdown

Fortunately, that analysis will continue even in the face of a threatened government shutdown, the Fermilab website assures. But if a budget agreement isn’t reached by midnight tonight, business won’t continue as usual for many scientists, beginning with the 6,000 employees of the National Institutes of Health. As for extramural research that relies upon federal dollars, most ongoing clinical trials will be unperturbed, experts said. But Johns Hopkins researchers said that no new clinical trials will be able to start during the shutdown, and the Medical Center’s Richard Schilsky told MedPageToday that he’s concerned about obtaining experimental drugs from the National Cancer Institute.

“The biggest issue for us would be studies of investigational drugs being supplied by the National Cancer Institute,” he said in an email. “Many times we have to order drugs for each unique patient to be treated, and if NCI shuts down and can’t ship the drug, then we can’t treat the patient!”

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The unsung heroes of scientific research are the graduate students*. Graduate students provide the enthusiasm to run experiments 7 days a week and all hours of the day and night to generate data for publications and their own thesis projects. The fresh perspective a graduate student brings to an area of research can also provide new ideas to their mentors and collaborators, spotting connections or opportunities that might have been missed by those with more experience. In even the biggest discoveries, graduate students play a critical role.

That was the take-home message from Neil Shubin’s keynote lecture at last week’s Scientific Diversity: People, Research, Careers Symposium organized by the Biological Sciences Division. Following talks by graduate students, post-docs, and young professors, Shubin delivered a characteristically fascinating and funny tale about his laboratory’s discovery in 2004 of Tiktaalik, an important transitional fossil between sea and land animals. The story of Tiktaalik may have been familiar if you’ve read Shubin’s excellent Your Inner Fish or seen him speak before. But this time around, Shubin put added emphasis on the critical role of his graduate students and collaborators, both in setting the stage for the fossil’s excavation and in the continued quest to learn from Tiktaalik’s remains.

In fact, Shubin said the very spark for Tiktaalik’s discovery came from a friendly argument between him and his former graduate student at the University of Pennsylvania, Ted Daeschler. Shubin and Daeschler had found many Devonian era fossils of fish with primitive limb-like structures in their home state, but wanted to find even earlier examples of the transition from fins to limbs. So they had to pick the right place for an expedition, with exposed rocks of the right age for finding such an elusive fossil.

“Everything changed for us in a conversation in my office in 1998. We were having an argument, as graduate students and their advisors typically do, and we settled the debate with a college geology textbook,” Shubin said. “I was thumbing through the book, and I hit a diagram that changed the course of my career.”

The diagram showed the three areas where the ancient deltas Shubin was seeking were known to be exposed. Two of them had already been the site of expeditions, but the third - a cluster of islands in the Canadian arctic - was largely unexplored. Shubin and Daeschler “ran to the library,” he said, and found a paper that confirmed the region held the exact type of rock they were looking for.

“It was truly exciting; here was a whole part of the world that was unexplored,” Shubin said. “After we saw this, we went to Chinese food for lunch, and my fortune cookie said, ‘Soon you will be at the top of the world.’”

It took six more years for an expedition to find Tiktaalik, embedded in the rocks of Ellesmere Island. It took a further two years for the fossil to be prepared sufficiently (by preparator Robert Masek) for analysis and publication. The rest is history - massive media coverage, a book, and even The Colbert Report. But the story of Tiktaalik isn’t over, and it is graduate students that are writing the newest chapters.

“It’s really a nice system, because so many bones are so well preserved, for us to ask new kinds of questions, and this is where graduate students come in,” Shubin said.

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Despite what beer commercials tell you, not everyone responds to alcohol in the same way. For some people, an alcoholic drink is a party-starter, increasing energy and sociability. For others, a drink can be a party-ender, producing feelings of fatigue and sluggishness. In pharmacological terms, alcohol is a mixed stimulant/depressant, able to produce a wide range of behavioral effects. But does an individual’s place on this spectrum of alcohol response predict more than their night on the town? Can it say something about their future potential to binge drink, or abuse alcohol in other ways?

Classically, psychiatrists have linked an individual’s alcohol response to their potential for abuse through one simple word: tolerance. According to the low-level response theory,  reduced “intoxicating” effects of alcohol were associated with heavier drinking, as individuals have fewer internal cues warning them to stop. But the experiments that informed the low-level response theory focused on the depressant effects of alcohol, measuring predominantly sedation in test subjects. What about the positive and rewarding effects that inspire some people to drink in the first place?

“What is intoxication? It’s really bi-modal,” said Andrea King, professor of psychiatry and behavioral neuroscience at the Medical Center. “Some people can think intoxication is great - you’re drunk, it’s fun - while others think of it as something bad, that it’s a toxic reaction.”

King studied both of those alcohol responses in a 2002 study, giving heavy and light drinkers a disguised drink in a laboratory and asking the how it made them feel on a variety of measures. The study found that heavy drinkers were indeed more likely to report positive and rewarding effects of alcohol, even when they didn’t know it was alcohol they were drinking. From that small study, King and her team sought to both expand their subject pool and follow participants for years to see how their acute responses in the lab tests might predict their future drinking behavior.

The first data from that epic undertaking - a two-year followup of nearly 200 subjects aged 21 to 35 - was published yesterday in Archives of General Psychiatry. True to King’s hypothesis, an individual’s response to a mystery drink was predictive of how their drinking behavior evolved over the following two years, with both stimulant and sedative effects playing a role. While some subjects who were heavy drinkers at the time of the original experiments curtailed their binge drinking episodes, others demonstrated an “exacerbating” trajectory, binge drinking more frequently - up to half of the days in a month.

The path a subject followed could be foretold by their acute response to alcohol in the lab. Subjects with both higher sensitivity to the rewarding effects of alcohol and lower sensitivity to its depressant effects were found to have the most alcohol problems in the follow-up period. Those subjects drank more and more often, increased the frequency of binge drinking, suffered more alcohol-related consequences, and were more likely to qualify for a diagnosis of an alcohol-use disorder.

“The results change our thinking about how alcohol responses affect the development of an alcohol-use disorder,” King said. “It’s not just overall tolerance, but also sensitivity to alcohol’s euphoric effects that increases risk for excessive drinking.”

This new theory, dubbed a “modified differentiator theory” in King’s paper, could be a game-changer for how substance abuse experts identify people at-risk for alcohol problems.  Those who respond very positively to an alcoholic drink might be warned early on that they are at elevated risk for drinking problems.

“If we know more about who’s going to become a problem drinker, we may be able to prevent future escalations and intervene earlier, before development of severe alcoholism,” King said. “The stimulant-type responder could learn that while such a response pattern may not be their fault, it could put them at risk for longer-term problems and consequences.”

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In taking care of sick patients, clinicians have two goals: treating the disease and treating the symptoms. In the case of an infection or a chronic illness, accomplishing this dual purpose is relatively straightforward. But what about when the symptom is something more complicated than pain or nausea? Some genetic disorders carry the consequence of short height, a condition that may have more serious social effects than medical. But clinicians are nevertheless finding new ways to “treat” short height, helping children approach, if not fully reach, the size of their peers.

One genetic syndrome that carries the symptom of short stature is Turner syndrome, the result of a missing or incomplete X chromosome that occurs in 1 in 2,000 female births. In addition to some physical and reproductive abnormalities, Turner patients grow to an average of about 4-foot-7, several inches below the typical height for an adult female. Since 1996, the FDA has approved the use of growth hormone to help Turner patients achieve a closer-to-normal height, and the treatment, while very expensive, has achieved some success. But a new study finds that a second hormone, once thought to stunt growth rather than promote it, might be a useful additive in the treatment of short stature.

Estrogen is prescribed for a variety of medical uses, such as birth control, hormone replacement during menopause, but also as a suppressor of growth in teenage girls. However, the doses of estrogen given via pills or patches are much higher than what the body normally releases into the bloodstream. Some clinicians, including Robert Rosenfield, professor emeritus of adult and pediatric endocrinology, believe that these lower doses of estrogen may actually promote growth, particularly in Turner girls who have a deficiency of the hormone. But many doctors have shied away from giving Turner girls estrogen, he said.

“It’s obvious that normal girls have a growth spurt, and it turns out to be due to estrogen,” Rosenfield said. “But because of this long history of estrogen being seen as a growth inhibitor, people have delayed given estrogen in Turner syndrome until girls were maybe 14 or 15 years old because they didn’t want to rob girls of the growth-promoting benefits of hormone treatment.”

That theory was put to the test in a long-running and controversial study published last week in the New England Journal of Medicine. Nearly 150 girls with Turner syndrome were divided into different height-treatment groups: growth hormone alone, estrogen alone, growth hormone and estrogen, or placebo (this fourth group created some of the controversy, as the girls were not aware that they were receiving no treatment). The treatments were started when the girls were as young as 5 years old until their growth slowed in their teens, signaling that they had reached their adult height.

Between 1987, when the study began, and today, when the study was finally completed and published, the use of growth hormone in Turner girls has become accepted and approved. In fact, as far as growth hormone use goes, the good news of this study was no news, as the effect of GH alone on height was right in line with other, less rigorous studies conducted in Turner girls. The average size of that effect was not staggering: about 5 centimeters, or 2 inches, over the 7 years of treatment.

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